Small Molecule · REL-1017

Esmethadone (REL-1017)

DiscontinuedRelmada Therapeutics, Inc. (RLMD)

Oral, once-daily small molecule; the opioid-inactive (S)-(+)-dextro-enantiomer of methadone (dextromethadone / d-methadone). A low-affinity, low-potency, high-trapping uncompetitive NMDA receptor (NMDAR) channel blocker that binds the MK-801 site and preferentially blocks pathologically hyperactive GluN2D-containing receptors under physiological magnesium, hypothesized to restore neural plasticity as a rapid antidepressant without ketamine-like dissociative or opioid effects. Developed by Relmada Therapeutics as an adjunctive (and earlier monotherapy) treatment for major depressive disorder; after a positive Phase 2a the three pivotal RELIANCE Phase 3 studies failed and development was discontinued (RELIANCE-II/RELIGHT halted Dec 2024; license terminated and asset returned to the inventors Jul 2025).

Also known as: REL-1017, dextromethadone, d-methadone, esmethadone, (S)-(+)-methadone, 5653-80-5

Data current as of

Modality
Small molecule
Chemical class
Aminoketone, Diphenylpropylamine
DEA schedule
Schedule II
Chemistry
Single enantiomer
Mechanism
GluN2D antagonist
Highest phase
Discontinued
Lead indication
Major depressive disorder
Developer
Relmada Therapeutics, Inc. (RLMD)
Trials
6 tracked · 146 sites

Mechanism of action

Low-affinity, low-potency, high-trapping uncompetitive NMDA receptor (NMDAR) antagonist that binds the MK-801 (channel) site in an activity- and use-dependent manner. In recombinant human heterodimeric NMDARs in physiological (1 mM) Mg2+, esmethadone is most potent at GluN1/GluN2D (IC50 ~13.5 uM) and least potent at GluN1/GluN2A (IC50 ~63.1 uM), i.e. it preferentially blocks GluN2D-containing receptors (Bettini et al., Pharmaceuticals 2022). As the opioid-inactive (S)-enantiomer of methadone it lacks meaningful opioid activity and showed no abuse potential, no withdrawal, and no psychotomimetic effects clinically. The rapid-antidepressant hypothesis is restoration of physiological plasticity via tonic block of pathologically hyperactive GluN2D NMDARs.

TargetActionAffinity
GluN2DprimaryGRIN2DAntagonistIC50 13.5 uMⓘ
NMDA receptorGRIN1Antagonist—ⓘ

Formulations

FormulationRouteRegimenPharmacokinetics
Esmethadone oral capsule
25 mg once daily maintenance dose, with a 75 mg loading dose on Day 1 (Phase 3 MDD adjunctive regimen)
OralOnce dailyt½ 36.3 h · Tmax 2.5 h

Development timeline

DiscontinuedDec 2024 – Jul 2025
  1. Relmada terminated the esmethadone license agreement and returned the REL-1017 technology to its inventors (Charles Inturrisi & Paolo Manfredi / Levomecor Inc.), formally ending Relmada's REL-1017 development in MDD.↗
  2. missedRelmada discontinued RELIANCE-II and RELIGHT after a DMC review found RELIANCE-II unlikely to meet its primary endpoint.↗
Phase 3Jan 2021 – Dec 2022
  1. missedRELIANCE-I adjunctive missed its primary MADRS Day 28 endpoint (REL-1017 -15.1 vs placebo -12.9, not significant).↗
  2. missedRELIANCE-III monotherapy missed its primary MADRS Day 28 endpoint (REL-1017 -14.8 vs placebo -13.9).↗
  3. Phase 3 RELIANCE program initiated (RELIANCE-I adjunctive first patient; RELIANCE-II, RELIANCE-III monotherapy, and open-label safety studies followed in 2021).
Phase 2Sept 2019
  1. Phase 2a, 7-day adjunctive proof-of-concept (NCT03051256, n=62, 25 or 50 mg/day) completed; reported rapid, robust, sustained antidepressant signal vs placebo, supporting advancement to Phase 3.

Esmethadone (REL-1017) for Major depressive disorder

DiscontinuedDiscontinuedMajor depressive disorder indication →

Phase 3 RELIANCE program of REL-1017 in MDD, studied both as adjunctive therapy (RELIANCE-I, RELIANCE-II, RELIGHT) for patients with inadequate response to standard antidepressants and as monotherapy (RELIANCE-III), supported by an open-label long-term safety study (RELIANCE-OLS). Following a positive Phase 2a adjunctive study (NCT03051256, 7-day dosing), all three pivotal studies that read out failed the primary MADRS endpoint: RELIANCE-III monotherapy (NCT05081167) missed on 13 Oct 2022 (REL-1017 -14.8 vs placebo -13.9, high placebo response) and RELIANCE-I adjunctive (NCT04688164) missed on 7 Dec 2022 (-15.1 vs -12.9, not statistically significant). On 9 Dec 2024, after a Data Monitoring Committee review of the full RELIANCE-II dataset indicated it was unlikely to meet its primary endpoint, Relmada discontinued the RELIANCE-II (NCT04855747) and RELIGHT (NCT06011577) Phase 3 studies. On 7 Jul 2025 Relmada terminated the esmethadone license and returned the asset to its inventors (Levomecor Inc.), formally ending Relmada's development of REL-1017 in MDD. REL-1017 was consistently safe and well tolerated, with no opioid-like, withdrawal, or psychotomimetic effects.

Readouts

  • Date TBDCancelledTopline datamissedNCT04855747

    Relmada discontinued RELIANCE-II and RELIGHT after a DMC review found RELIANCE-II unlikely to meet its primary endpoint. ↗

  • 2022-12-07ReportedTopline datamissedNCT04688164

    RELIANCE-I adjunctive missed its primary MADRS Day 28 endpoint (REL-1017 -15.1 vs placebo -12.9, not significant). ↗

  • 2022-10-13ReportedTopline datamissedNCT05081167

    RELIANCE-III monotherapy missed its primary MADRS Day 28 endpoint (REL-1017 -14.8 vs placebo -13.9). ↗

Clinical trials

NCT06011577RELIGHTPhase 3Discontinuedn=27

Randomized, Double-Blind, Placebo-Controlled Trial of REL-1017 as Adjunctive Treatment for MDD (RELIGHT)

Started Sept 2023· 📍 36 sites across 1 country (United States)

missedprimaryMADRS total score change from baseline (adjunctive)

Terminated on 9 Dec 2024 alongside RELIANCE-II; only ~27 of a planned cohort had enrolled. No efficacy readout — stopped as part of the program discontinuation following the RELIANCE-II DMC review.

NCT05081167REL-1017-303 (RELIANCE-III)Phase 3Completedn=232

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of REL-1017 Monotherapy for Major Depressive Disorder (RELIANCE-III)

Started Jun 2021· Primary completion Sept 2022· 📍 10 sites across 1 country (United States)

missedprimaryMADRS total score change from baseline to Day 28 (monotherapy) — REL-1017 -14.8 vs placebo -13.9 (~0.9-point difference)

Did not achieve a statistically significant separation from placebo on the primary MADRS Day 28 endpoint amid a higher-than-expected placebo response. A post-hoc 'band-pass' analysis excluding outlier sites showed >4.9-point difference (p<0.05), but this was exploratory. Safety/tolerability favorable.

NCT04855760REL-1017-304 (RELIANCE-OLS)Phase 3Completedn=627

A Phase 3, Multicenter, Open-Label Study to Assess the Long-Term Safety of REL-1017 as a Treatment of Major Depressive Disorder

Started Apr 2021· Primary completion Jul 2023· 📍 9 sites across 1 country (United States)

metprimaryIncidence of treatment-emergent adverse events (long-term safety, open-label)

Open-label long-term safety study (n=627); no placebo comparator and no efficacy primary endpoint. REL-1017 was generally safe and well tolerated over extended dosing.

NCT04855747REL-1017-302 (RELIANCE-II)Phase 3Discontinuedn=236

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of REL-1017 as Adjunctive Treatment of Major Depressive Disorder (RELIANCE-II)

Started Mar 2021· Primary completion Dec 2024· 📍 70 sites across 1 country (United States)

missedprimaryMADRS total score change from baseline (adjunctive)

Terminated ('Program Discontinued') on 9 Dec 2024 after a DMC review of the full dataset indicated it was unlikely to meet its primary endpoint; no separate efficacy topline with effect sizes was reported. CT.gov lead sponsor now displays 'Levomecor Inc.' following the 2025 asset handover, but the study was conducted by Relmada.

NCT04688164REL-1017-301 (RELIANCE-I)Phase 3Completedn=227

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of REL-1017 as Adjunctive Treatment of Major Depressive Disorder (RELIANCE-I)

Started Jan 2021· Primary completion Nov 2022· 📍 11 sites across 1 country (United States)

missedprimaryMADRS total score change from baseline to Day 28 (adjunctive) — REL-1017 -15.1 vs placebo -12.9 (2.2-point difference)

Missed the primary endpoint: the 2.2-point MADRS advantage for REL-1017 (n=113) vs placebo (n=114) was not statistically significant. A key secondary response-rate analysis was significant (39.8% vs 27.2%, p<0.05). Results later published in J Clin Psychiatry.

NCT03051256REL-1017-202Phase 2Completedn=62

Phase 2a Multicenter Randomized Double-Blind Placebo-Controlled Study to Assess the Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing of REL-1017 as Adjunctive Therapy in the Treatment of Patients Diagnosed With MDD

Started May 2018· Primary completion Jul 2019· 📍 10 sites across 1 country (United States)

metprimaryTreatment-emergent adverse events (safety/tolerability) over 7-day adjunctive dosing

Primary endpoint was safety/tolerability; REL-1017 (25 or 50 mg/day) was well tolerated with no opioid-like effects. Exploratory efficacy showed a rapid, robust, sustained antidepressant signal vs placebo, supporting Phase 3.

Conference coverage

REL-1017 appears in 6 CNS Pulse conference abstracts:

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Identifiers

Sources

  1. Drug-Drug Interaction Studies of Esmethadone (REL-1017) Involving CYP3A4- and CYP2D6-Mediated Metabolism — Clinical Pharmacology in Drug Development (PMC)
  2. Pharmacological Comparative Characterization of REL-1017 (Esmethadone-HCl) and Other NMDAR Channel Blockers in Human Heterodimeric NMDA Receptors — Bettini et al., Pharmaceuticals (Basel) 2022;15(8):997 (PMC)
  3. RELIANCE-I: REL-1017 adjunctive Phase 3 in MDD (NCT04688164) — ClinicalTrials.gov
  4. RELIANCE-II: REL-1017 adjunctive Phase 3 in MDD — terminated (NCT04855747) — ClinicalTrials.gov
  5. RELIANCE-III: REL-1017 monotherapy Phase 3 in MDD (NCT05081167) — ClinicalTrials.gov
  6. RELIANCE-OLS: REL-1017 open-label long-term safety Phase 3 in MDD (NCT04855760) — ClinicalTrials.gov
  7. RELIGHT: REL-1017 adjunctive Phase 3 in MDD — terminated (NCT06011577) — ClinicalTrials.gov
  8. Relmada announces RELIANCE-I adjunctive topline results (primary endpoint not met) — Relmada Therapeutics / IR
  9. Relmada announces RELIANCE-III monotherapy topline results (primary endpoint not met) — Relmada Therapeutics / IR
  10. Relmada terminates license agreement for troubled phase 3 depression asset — Fierce Biotech
  11. Relmada to discontinue the RELIANCE-II and RELIGHT Phase 3 studies of REL-1017 — Relmada Therapeutics / IR
  12. Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing With 25 mg or 50 mg Daily of REL-1017 in MDD — ClinicalTrials.gov